Two-dimensional gel electrophoresis of the changes in nucleoprotein of rat liver was extended through the development of computerized quantitation of the different proteins. Of some 500 proteins, 102 either disappeared or were markedly reduced in livers from hypothyroid rats. These changes are the greatest in number and in quantity ever reported as an effect of thyroid hormone. Additional studies on post-transcriptional modification of nucleoproteins showed that thyroidectomy inhibited acetylation, phosphorylation and ADP ribosylation of many of these proteins. Since some of these reactions may affect gene activity and since, in general, actively transcribed genes are more sensitive to DNase I and micrococcal nuclease, we investigated the effect of thyroid states on chromatin sensitivity to nucleases. We found that hypothyroidism was associated with decreased solubilization of liver chromatin to both DNase I and micrococcal nuclease.